There has been recent concern about the reduced efficacy of Clopidogrel on platelet inhibition when a Proton Pump Inhibitor (PPI) is co-prescribed (Omeprazole in particular). There are conflicting results as to whether this drug interaction leads to an excess of adverse clinical cardiovascular outcomes. A Randomised Control Trial in the New England Journal of Medicine has now reported that prophylactic prescribing of Omeprazole in patients with CAD also taking dual anti-platelet therapy (Aspirin and Clopidogrel) significantly reduced the rate of adverse upper GI events withought significantly increasing adverse CV events[1].

Over the past decade Clopidogrel has become an established anti-platelet agent in the management of acute coronary syndromes and following both elective and non-elective PCI. Furthermore Clopidogrel with or withought aspirin has proven efficacy in the treatment atherothrombotic disease (Cerebral and peripheral vascular disease).

Clopidogrel inhibits platelet aggregation by irreversibility antagonising the effects of ADP on the platelet P2Y12 receptor. It requires conversion to an active metabolite, by the cytochrome P450 enzyme system (liver), which is also utilised by several other drugs and thus partly explains the potential for interactions between several drugs and Clopidogrel. Furthermore the P450 system consists of several isoenzymes but the CYP219 in particular has received significant attention as a loss of function variants have been identified that result in a poor response to Clopidogrel and predict an adverse prognosis[2].

In 2008 a double-blind RCT reported that patients undergoing PCI receiving dual anti-platelet therapy, when co-administered Omeprazole (20mg/d) had significant reduction in platelet reactivity (ex-vivo) after 7 days compared to placebo[3]. A number of further studies confirmed that indeed platelet responsiveness to Clopidogrel was diminished with a PPI, particularly Omeprazole [4-6], however only some studies confirmed that this mechanistic interaction translated into clinically significant adverse outcomes[7] whereas others did not[8] . Evidence for adverse effects came primarily from observational studies, which were probably confounded by the fact that patients also taking a PPI at the time of Clopidogrel could have greater co-morbidities and thus be at higher risk anyway [9]. The drug interactions led some to stagger the dose of Clopidogrel and PPI , although recent evidence would suggest no advantage of this approach [10] A meta-analysis in JACC, from July 2010 (covered in a earlier BCS editorial this year) reported that a significant interaction was seen primarily in high risk patients (annual MACE rate >10%) [11] Furthermore recent evidence suggests that the use of a PPI identifies a group of individuals at higher risk of MACE, independent of Clopidogrel use[12] In 2009 both the European (EMEA) and US (FDA) licensing authorities advised warnings and discouraged the use of this drug combination.

Thus the investigators of the Clopidogrel and the Optimisation of Gastrointestinal Events Trial(COGENT) aimed to address this further by testing the safety and efficacy of Omeprazole in patients with CAD who were also taking dual antiplatelet therapy. Furthermore they also tested whether prophylactic use of a PPI in patients reduced upper GI complications whilst taking dual antiplatelet therapy. They performed a multi-centre international double blind placebo controlled study to test the efficacy of a fixed dose combined pill containing Clopidogrel (75mg) and Omeprazole (20mg) as compared with Clopidogrel alone. All patients received Aspirin (75-325mg)

The study was undertaken in 2008 at 393 sites in 15 countries and initially planned to recruit 5000 patients but ended prematurely after n=3873 because the study sponsor (Cogentus pharmaceuticals) lost its financial backing and went bust. Patients were followed up for median 106 days (IQR 55-166, max 341)

The primary endpoints of the trial are listed in the table below.

Baseline characteristics of each group (n=1876 Omeprazole group v n=1885 in the placebo arm) were well balanced with median age 68yrs, 70% having had PCI, 42% ACS and 30% MI prior to recruitment. Approx. 80% had hypertension, 30% diabetes, 50% were current alcohol users. Over 50% had negative serology for H.Pylori and only 4% of patients had suffered a prior GI bleed. Over 65% were taking a statin and 8% an NSAID at baseline.

RESULTS

Compliance for the Omeprazole/Clopidogrel combination was 84.5% and 83.3% for placebo.

Outcome at 180 days

Omeprazole n=1876

Placebo

n=1885

Event rate (Omep v placebo)

Cox Hazard ratio

(95% CI)

Composite of GI events*

13

38

1.1% v 2.9%

P<0.001

0.34 (0.18-0.63)

P<0.001

Overt GI Bleed

1

8

0.1 v 0.6%

p<0.03

Overt GI bleed but unknown origin

1

7

0.1 v 0.6%

p<0.03

Composite CV event (MI, stroke, CV death, revasc)

55

54

4.9 v 5.7%

P=0.98

0.99 (0.59-1.38)

P=0.64

MI

14

15

1.2 v 1.5%

P=0.83

0.92 (0.44-1.9)

P=0.81

Revascularisation

42

45

4 v 4.6%

P=0.70

0.91 (0.59-1.38)

P=0.64

CV death

5

3

0.4 v 0.3%

P=0.49

The combination pill of Clopidogrel and Omeprazole significantly reduced the composite of GI events* (upper GI bleeding identified or of unknown origin, occult bleeding with a drop in Hb>2g/dl, symptomatic ulcer, upper GI pain with >5 GI erosions on endoscopy). The absolute risk reduction was 1.8%. Thus 55 patients would need to be treated with this combination for 6 months to prevent one adverse composite GI endpoint, in contrast to a NNT of 98 to prevent one GI bleed. No significant difference in rates of adjudicated CV end points was seen. Only 2 cases of stent thrombosis were seen and these were both in the placebo group. Diarrhoea was more frequent in the Omeprazole group (3% vs. 1.8% p=0.01) but no cases of c-difficle were identified.

The COGENT study is the only RCT to demonstrate that prophylactic use of Omeprazole in the setting of dual antiplatelet therapy in patients with CAD significantly reduces GI events. Furthermore the study demonstrated no significant increase risk in CV events.

Limitations of the trial include reduced power and low event rates due to a somewhat lower risk population overall and also because the trial was stopped early. Given the recent reports of CYP2C19 mutations (homozygous in 2-3% of the population) and reduced Clopidogrel responsiveness the authors acknowledged that a larger study would be required to confirm this in the context of a PPI. The study goes someway to refute the findings of previous observational studies but in the context of recent work[11] would suggest that in lower risk patients the addition of PPI to Clopidogrel and aspirin does not increase CV risk and yet significantly reduces GI bleeding.

REFERENCES

Bhatt, D.L., et al., Clopidogrel with or without Omeprazole in Coronary Artery Disease. New England Journal of Medicine. 0(0).PUBLISHED ONLINE 6th October 2010.

O'Donoghue, M.L., et al., Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet, 2009. 374(9694): p. 989-97.